All mammalian species contain a very large number of endogenous genomic retrovirus elements acquired by germline infection over the course of evolution. In humans retroviral elements represent approximately 8% of the genome and their number approaches the total number of encoded genes. Many endogenous retrovirus elements are defective, however some contain an entire complement of functional viral genes characteristic of replication-competent exogenous retroviruses. Although the expression of most endogenous retroviruses is largely suppressed in the host, the production of retroviruses or their gene products during development and during certain physiological or pathological states is well documented. Little is known about the control of retrovirus expression or the influence of such expression on the physiology or pathology of the host. An extensively investigated group of endogenous retroviruses are those giving rise to polytropic MLVs in mice. Polytropic MuLVs are formed by recombination of ecotropic MuLVs with endogenous envelope sequences present in the genomes of inbred mouse strains. The viruses exhibit an altered infectious host range and utilize a cell surface receptor distinct from the receptor utilized by ecotropic MuLVs. In several instances polytropic MuLVs have been directly implicated in pathogenesis, including the induction of proliferative, immunological, and neurological disorders. The generation of variants after infection results in a mixed retrovirus infection. One aspect of the project involves studies of the interactions of retroviruses in mixed infections. Upon co-inoculation of polytropic and ecotropic MuLVs in mice we have observed profound effects on the infectious spread of the polytropic virus, concomitant with a very rapid induction of neurological disease not observed after inoculation with either virus alone. A common effect of mixed infections resulting in neurological disease is a greatly enhanced spread of the polytropic virus in tissues peripheral to the central nervous system (CNS). This phenomenon is mediated by pseudotyping of polytropic viral genomes within ecotropic virus particles. Neurological disease is evident in mice inoculated as a mixture of ecotropic MuLVs with a number of different polytropic MuLVs, suggesting that neuropathogenicity may be a general property of polytropic MuLVs. Another aspect of our studies involves the characterization of the family of endogenous sequences that are homologous to the sequences found in recombinant polytropic MLVs and the precise identification of those endogenous retroviruses that participate in recombination. Different ecotropic viruses specifically recombine with different endogenous proviruses to give rise to the recombinants. Determination of the precise sequences that participate in recombination is essential to understanding characteristics of the endogenous viruses that facilitate this process. Such identification has been elusive because of the very close similarity of the endogenous viruses as well as the rapid rate of evolution of the viruses during replication. We have isolated most of the endogenous proviruses in NFS/N mice that could potentially give rise to the recombinant viruses. Most of the proviruses contain intact sequences encoding the receptor-binding region of the envelope protein and could be distinguished by sequence heterogeneity within that region. Furthermore, three major groups of endogenous proviruses were identified that included a new group of endogenous viruses that have properties of progenitors to the polytropic proviruses that have thus far been described. The ability to distinguish the proviruses by sequence heterogeneity has facilitated the unambiguous identification of proviruses that participate in the generation of polytropic MLVs after inoculation of Moloney MLV (M-MLV), an ecotropic MLV that induces lymphocytic leukemia. Our analyses indicate that the majority of M-MLV-derived recombinant viruses arise from only three endogenous proviruses, one of which corresponds to a member of the newly described group of progenitor proviruses. Furthermore, polytropic MLVs are frequently generated by multiple recombination events involving the env genes of more than one provirus. The latter observation suggests that defective proviruses may complement one another to generate functional recombinants with ecotropic MLVs and that the recombinant MLVs may evolve in the M-MLV-infected host to more replication-proficient and/or more virulent forms.